Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/72—Two oxygen atoms, e.g. hydantoin
  • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems

Definitions

• the invention is in the field of cancer therapeutics, such as processes for the synthesis of prostate cancer therapeutics.
• prostate cancer is the most commonly diagnosed cancer among men in the United States, other than skin cancer.
• the American Cancer Society estimates that approximately 186,000 new cases of prostate cancer were diagnosed, and approximately 29,000 men died of prostate cancer in the United States alone during 2008. Prostate cancer is thus the second-leading cause of cancer death in men in the United States, after lung cancer.
• Metastatic prostate cancer is cancer that has spread beyond the prostate and surrounding tissues into distant organs and tissues. The majority of men who die from prostate cancer die from the consequences of metastatic disease. According to the National Cancer Institute, the median survival of patients with prostate cancer that has metastasized to distant organs is usually one to three years, and most such patients will die of prostate cancer. Metastatic prostate cancer is generally divided into two states: the hormone-sensitive state and the castration-resistant state (also referred to as the hormone-refractory state).
• Testosterone and other male sex hormones can fuel the growth of prostate cancer cells. Androgens exert their effects on prostate cancer cells by binding to and activating the androgen receptor, which is expressed in prostate cancer cells. When they first metastasize to distant sites, most prostate cancers depend on androgens for growth. These prostate cancers are known as “hormone-sensitive” cancers. Accordingly, the leading therapies currently used for the treatment of metastatic prostate cancer are focused on diminishing, or antagonizing, the effects of androgens on prostate cancer cells. One approach utilizes so-called “anti-androgens,” which are molecules that block the interaction of androgens with the androgen receptor.
• Another approach is to reduce the amount of androgens produced in the body, primarily in the testes. This can be achieved surgically by removal of both testicles (orchiectomy) or through use of drugs known as luteinizing hormone-releasing hormone, or LHRH, agonist drugs, which lower the native production of testosterone in the testicles (sometimes called “chemical castration”).
• LHRH luteinizing hormone-releasing hormone
• prostate cancers In experiments comparing gene expression in hormone sensitive and castration-resistant prostate cancer cells, an increase in androgen receptor expression was the only gene change consistently associated with castration-resistant disease [Chen, C. et al. “Molecular determinants of resistance to antiandrogen therapy.” Nat. Med. (2004), 10(1):33-39].
• prostate cancers Once in this state, prostate cancers generally continue to grow in an androgen-dependent manner despite the reduction of testosterone production to very low (i.e., post-castration) levels.
• Prostate cancer in this state is known as “castration-resistant” prostate cancer, or CRPC.
• the switch from the hormone-sensitive to the castration-resistant state following initiation of hormonal therapy is generally determined based on either rising levels of prostate-specific antigen, or PSA, or documented disease progression as evidenced by imaging tests or clinical symptoms.
• PSA prostate-specific antigen
• Metastatic prostate cancer that has become castration-resistant is extremely aggressive; these patients have a median survival of only 10 to 16 months.
• CRPC CRPC metastatic prostate cancer
• therapies currently used for the treatment of metastatic prostate cancer operate by reducing the ability of androgens to fuel the growth of prostate cancer cells, they generally are effective only on prostate cancers that remain hormone-sensitive by depending on androgens for growth.
• CRPC no longer responds to hormonal therapies that are effective in the hormone-sensitive state.
• drugs that initially block the androgen receptor and inhibit growth of hormone sensitive prostate cancer may have precisely the opposite effect and start to fuel the growth of CRPC.
• Casodex® (bicalutamide), sold by AstraZeneca PLC, directly blocks the interaction of androgens with the androgen receptor and is the largest selling of the anti-androgen therapies.
• Casodex® failed effectively to inhibit the androgen receptor in these cells, and in some cases it became a stimulant of the androgen receptor.
• the synthetic route to compounds of the invention comprises the coupling of an isothiocyanate with an isobutyronitrile.
• the main drawbacks of the process as previously described include only a 25% yield of desired product being achieved in the final step, resulting in a 15% overall yield from commercially available starting materials.
• each intermediate compound requires laborious column chromatography for purification, resulting in extended overall production time which is industrially disadvantageous.
• the present invention described herein comprises a 50% overall yield, and any required purification is achieved by simple precipitation or crystallization means.
• the present invention avoids the use of the extremely toxic reagent acetone cyanohydrin.
• the process according to the present invention is a safer process in which the amount of solvent is lowered, minimizing waste and environmental impact, the cycle time is reduced, and the throughput and overall yield of the process is increased.
• the present invention comprises a highly efficient process for making a compound of formula (I, 2-I):
• LG is Br or I. In a particular embodiment, LG is Br.
• Another aspect of the present invention provides an efficient method of making an acid compound of formula (I, 2-Ia):
• L 1 is a single bond; and R 7 is —C( ⁇ O)—OH.
• 2-Ia, Y 1 and Y 2 are both methyl, R 7 is —C( ⁇ O)—OH, and R 2 is F.
• the above hydrolysis is carried out in the presence of concentrated HCl.
• the above hydrolysis is carried out at 80-140° C. or at about 80-140° C.
• the above hydrolysis is carried out at 120° C. or at about 120° C.
• the above hydrolysis is carried out for 10-60 hr or for about 10 hr to about 60 hr.
• the above hydrolysis is carried out for 48 hr or for about 48 hr.
• 2-Ia, Y 1 and Y 2 are both methyl, R 7 is —C( ⁇ O)—OH, R 2 is F, and X is S.
• 2-Ia, Y 1 and Y 2 are both methyl, R 7 is —C( ⁇ O)—OH, R 2 is F, and X is O.
• the present invention comprises a highly efficient process for making a compound of formula (I):
• LG is Br, I or another good leaving group, with a compound of formula B:
• LG is Br or I. In a particular embodiment, LG is Br.
• the present invention comprises a highly efficient process for making a compound of formula (I):
• L 1 is a single bond.
• L 1 is —CH 2 —, —CH 2 —CH 2 —, or CH 2 —CH 2 —CH 2 —.
• L 1 is a single bond; and R 1 is —C( ⁇ O)—NHCH 3 .
• L 1 is a single bond; and R 1 is —C( ⁇ O)—NH 2 .
• R 2 is F.
• Y 1 and Y 2 are both methyl, R 1 is —C( ⁇ O)—NHCH 3 , and R 2 is F.
• R 1 is limited to -L 1 -(C ⁇ O)NH 2 , -L 1 -(C ⁇ O)NHR 4 , and -L 1 -(C ⁇ O)NR 4 R 5 , as hydrolysis of R 1 when R 1 is -L 1 -CN would result in hydrolysis of the other nitrile group present on the other benzene ring.
• L 1 is a nonentity (i.e., a single bond) as hydrolysis is depicted as resulting in a —COOH group, but in other embodiments, L 1 can also be C 1 -C 8 alkylene.
• the compound of formula C is treated with compound E, under amide bond-forming conditions to give the compound of formula G, which is followed by treatment with a reagent such as thiophosgene to form the compound of formula I (that is, the path C ⁇ G ⁇ I in the scheme above).
• a reagent such as thiophosgene
• a compound of formula A is mixed with a compound of formula B in the presence of a catalytic amount of both a copper (I) catalyst and a beta-dione ligand such as 2-acetylcyclohexanone, in a polar solvent and with heating to a temperature of about 90-120° C., about 100-110° C. or about 105° C.
• the copper (I) catalyst can be copper (I) chloride or copper (I) iodide.
• the copper (I) catalyst, such as CuCl can be present in an amount of about 0.05-0.35 equivalents with respect to compound A, about 0.15-0.25 equivalents with respect to compound A, or about 0.2 equivalents with respect to compound A.
• the ligand such as 2-acetylcyclohexanone
• the ligand can be present in an amount of about 0.05-0.35 equivalents with respect to compound A, about 0.15-0.25 equivalents with respect to compound A, or about 0.2 equivalents with respect to compound A.
• the ligand, such as 2-acetylcyclohexanone is present in an amount about equal to the amount of copper (I) catalyst, such as copper (I) chloride, used.
• Compound B can be added in an amount of about 1-2 equivalents with respect to compound A, about 1.25-1.75 equivalents with respect to compound A, or about 1.5 equivalents with respect to compound A.
• the polar solvent can be selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylacetamide (DMA), isopropylacetate (IPAc), isopropyl alcohol (IPA), and the like; in another embodiment, the polar solvent is DMF, water, or a mixture of DMF and water.
• DMSO dimethylsulfoxide
• DMF dimethylformamide
• NMP N-methylpyrrolidone
• DMA dimethylacetamide
• IPAc isopropylacetate
• IPA isopropyl alcohol
• the reaction mixture is then cooled to about 15-25° C., such as to about 25° C. or to room temperature.
• water is added to the cooled reaction mixture followed by washing with a water-immiscible organic solvent such as isopropyl acetate; the mixture is then separated into organic and aqueous layers.
• the aqueous layer is acidified to isolate compound C by precipitation, filtration and drying.
• the compound C is reacted with an alkylating agent of formula R 6 -LG, where R 6 is C 1 -C 8 alkyl and LG is Br, I, or another good leaving group, to form the compound of formula D.
• Compounds of formula R 6 -LG include compounds such as methyl iodide.
• the reaction can be conducted in the presence of an inorganic base, such as K 2 CO 3 , KHCO 3 , Na 2 CO 3 , or NaHCO 3 , in a polar solvent, such as DMSO, DMF, NMP, DMA, or IPAc, and with a catalytic amount of water.
• the catalytic amount of water can be about 5-25%, 10-20%, or 14% of the equivalents of compound C, or about 0.05-0.25%, 0.10-0.20%, or 0.14% of the volume of the polar solvent.
• the reaction mixture can be heated to about 35-50° C. or about 40-46° C., for about 5-60 min, or until analysis shows greater than about 90% or about 95% or about 99% conversion of compound C to compound D.
• the mixture can be cooled to about 5-25° C. or about 15-25° C.
• the reaction mixture containing compound D can be combined with water to precipitate the product D from solution.
• Product D can be isolated by filtration and drying.
• the amount of inorganic base used, such as K 2 CO 3 is about 2 equivalents or less than about 2 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 1.5 equivalents or less than about 1.5 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 1.2 equivalents or less than about 1.2 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 1.1 equivalents or less than about 1.1 equivalents relative to compound C.
• the amount of inorganic base used, such as K 2 CO 3 is about 1.0 equivalents or less than about 1.0 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 0.9 equivalents or less than about 0.9 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 0.8 equivalents or less than about 0.8 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 0.7 equivalents or less than about 0.7 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 0.6 equivalents or less than about 0.6 equivalents relative to compound C.
• CH 3 I when CH 3 I is used to generate D (where R 6 ⁇ CH 3 ) excess CH 3 I is quenched with acetic acid.
• CH 3 I can be used in about 1-1.5 equivalents relative to compound C, such as in an amount of about 1.2 equivalents relative to compound C, and an amount of AcOH can be added in about the amount of, or slightly more than, the excess amount of methyl iodide (for example, when 1.2 equivalents of methyl iodide are used, where methyl iodide is used in 0.2 equivalent excess relative to compound C, then about 0.21-0.25 equivalents, or about 0.23 equivalents, of AcOH relative to compound C can be used) to quench unreacted CH 3 I.
• Alternative methylating agents known to those skilled in the art, such as dimethylsulfate, can also be utilized for this step.
• the step of combining the reaction mixture containing compound D with water is carried out by gradually adding water to the warm reaction mixture over a time of about 0.5 hours to about 3.5 hours, about 0.6 hours to 3.4 hours, about 1 hours to 2 hours, or over a time of about 0.5, 0.6, 1, 2, 3, 3.4, or 3.5 hours, until about 1-5 volumes of water, or about 1-3 volumes of water, or about 2 volumes of water have been added (relative to the volume of the original reaction mixture), in order to precipitate compound D in a slower manner and reduce the amount of inorganic cation and base, such as K+, and CO 3 2 ⁇ from the inorganic base, such as K 2 CO 3 , that is used in the reaction.
• inorganic cation and base such as K+, and CO 3 2 ⁇ from the inorganic base, such as K 2 CO 3
• the added water is at a temperature of about 50° C. to about 80° C., about 50° C. to about 70° C., about 55° C. to about 75° C., about 55° C. to about 65° C., about 57° C. to about 63° C., about 48° C. to about 53° C., or about 68° C. to about 71° C., or about 57° C., or about 70° C.
• the precipitated compound D is re-suspended or re-slurried in water, and then the water is removed by filtration, in order to further reduce the amount of inorganic cation present.
• the volume of water for re-suspension or re-slurry is about 5-15 volumes, or about 10 volumes.
• the re-suspension or re-slurry is carried out for about 0.5 hours to about 3 hours, about 1.0 to about 2.0 hours, about 1.0 hour, about 1.5 hours, or about 2 hours.
• the temperature of the re-suspension or re-slurry water is about 15° C. to about 35° C., about 20° C. to about 30° C., about 20° C. to about 25° C., or about 20° C. to about 23 hi Va ° C.
• the residual amount of inorganic cation, such as potassium ion, remaining in compound D is less than or equal to about 1000 parts per million (ppm). In another embodiment, the residual amount of inorganic cation, such as potassium ion, remaining in compound D is less than or equal to about 500 ppm. In another embodiment, the residual amount of inorganic cation, such as potassium ion, remaining in compound D is less than or equal to about 300 ppm.
• the residual amount of base, such as bicarbonate ion, carbonate ion, or other base, remaining in compound D is less than or equal to about 1000 parts per million (ppm). In another embodiment, the residual amount of base remaining in compound D is less than or equal to about 500 ppm. In another embodiment, the residual amount of base remaining in compound D is less than or equal to about 300 ppm.
• compound D can be dried by blowing or sucking dry air, dry nitrogen or argon, or other dry inert gas, over the compound. In another embodiment, compound D can be dried by placing the compound under vacuum (such as under about 1 mmHg vacuum or less, 0.5 mmHg vacuum or less, or 0.1 mmHg vacuum or less). In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.5%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.3%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.1%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 500 ppm. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 300 ppm. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 100 ppm.
• An alternative method for formation of compound D from compound C utilizes standard Fischer esterification conditions comprising mixing compound C in methanol and heating for about 1-16 h at about 40-100° C. (or at reflux) with a catalytic amount of acid, such as one to five drops of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid or other mineral acid, p-toluenesulfonic acid, or sulfonic-acid-containing ion exchange resin; in one embodiment, H 2 SO 4 is used. Water can be removed by azeotropic distillation (such as by a Dean-Stark trap) in some embodiments. After esterification is complete (about 70%, about 80%, about 90%, about 95%, or about 99% completion), isolation of compound D can be performed as described above.
• a catalytic amount of acid such as one to five drops of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid or other mineral acid, p-toluenesulfonic
• the step of forming of compound I comprises mixing compound D with compound F in a polar solvent, or a mixture of a first polar solvent and a second polar solvent, and heating to about 60-100° C., about 80-100° C., or about 80-85° C., for a time of about 1-48 h or about 12-24 h.
• the process continues by cooling the reaction mixture to about 15-30° C., to about 25° C., or to room temperature, and combining with water, followed by extracting the desired product with a polar solvent, or a mixture of a third polar solvent and a fourth polar solvent.
• Compound F can be added in an amount of about 1-3 equivalents with respect to compound D, or about 1.5-2.5 equivalents with respect to compound D, or about 1.5 equivalents or about 2 equivalents with respect to compound D, or in an amount of about 1.5 equivalents, followed by an additional portion of about 0.5 equivalents as the reaction progresses.
• the combined organic extract layer can be reduced in volume and seeded with crystals of the desired product I to commence crystallization upon cooling to about 0-10° C. or about 3-6° C., followed by isolating the crystalline product by filtration, and then drying the product by streaming air over the product or in vacuo.
• the polar solvent or the first, second, third and fourth polar solvents, can be selected from the group consisting of DMSO, DMF, NMP, DMA, IPAc, MeCN, IPA, and the like.
• the polar solvent is DMF.
• the polar solvent is IPAc.
• the first polar solvent is IPAc
• the second polar solvent is DMSO.
• the third polar solvent is IPAc
• the fourth polar solvent is IPA.
• the first polar solvent is IPAc
• the second polar solvent is DMSO
• the third polar solvent is IPAc
• the fourth polar solvent is IPA.
• an alternative method for the formation of compound I involves two steps, outlined in the pathway the path C ⁇ G ⁇ I in the scheme above.
• the first step utilizes standard amide-bond formation conditions, comprising for example treating compound C with a coupling reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (AOP), benzotriazol-1-yloxytris(pyrrolidine)phosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxytris(pyrrolidine)phosphonium
• the polar solvent is, or the first and second polar solvents are, selected from the group consisting of DCM, DMSO, DMF, NMP, DMA, MeCN, and the like.
• the second step comprises a ring-closure reaction of compound G with a thiocarbonylation reagent such as thiophosgene, and heating the neat solution to about 60-120° C.
• the reaction is performed in a sealed-tube apparatus.
• Thiophosgene or a thiophosgene equivalent for example, 1,1-thiocarbonyl diimidazole
• compound I can be subjected to hydrolytic conditions when R 1 is a primary or secondary amide group, to produce the corresponding carboxylic acid derivative.
• substituent R 1 of the compound of formula A is —C( ⁇ O)—NH—R 4 .
• R 1 is —C( ⁇ O)—NH—CH 3 .
• substituent R 2 of the compound of formula A is fluorine.
• R 1 is —C( ⁇ O)—NH—R 4 and R 2 is fluorine.
• R 1 is —C( ⁇ O)—NH—CH 3 and R 2 is fluorine, and the compound of formula A is 4-bromo-2-fluoro-N-methylbenzamide.
• the compound of formula B is 2-aminoisobutyric acid (i.e., Y 1 and Y 2 are each CH 3 ). In another embodiment of the above method, the compound of formula B is 1-aminocyclobutanecarboxylic acid. In another embodiment of the above method, the compound of formula B is 1-aminocyclopentanecarboxylic acid.
• Y 1 and Y 2 are each CH 3 , R 1 is —C( ⁇ O)NHCH 3 and/or R 2 is F.
• Y 1 and Y 2 are each CH 3 , R 1 is —C( ⁇ O)NH 2 and/or R 2 is F.
• Variations of the compound of formula (I) are also provided.
• Compounds of formula (I) or a variation thereof as detailed herein or a pharmaceutically acceptable salt of any of the foregoing may find particular use in the treatment of prostate cancer, including CRPC and/or hormone-sensitive prostate cancer.
• the final product can be synthesized as follows (illustrated using the isothiocyanate):
• Y 1 and Y 2 are each CH 3 , and/or R 2 is F.
• the reaction can be run under basic conditions, with a trialkylamino base such as triethylamine present in about 2-5 equivalents, or about 3-4 equivalents, or about 3.4 equivalents, relative to compound C.
• Compound F 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, can be present in amounts of about 1.1-4 equivalents, or 1.1-2 equivalents, or about 1.5 equivalents, relative to compound C; alternatively, about 1.5 equivalents of compound F can be added, followed by another portion of about 0.5 equivalents as the reaction progresses.
• the solvent can be ethanol or another alcohol.
• the reaction mixture can be stirred for about 4-16 days, about 8-12 days, or about 10 days, at room temperature or elevated temperature. Afterwards, the reaction mixture can be concentrated, mixed with aqueous acid such as 1M HCl, and the product extracted with an organic solvent, such as ethyl acetate, to obtain the product M.
• the compound C is synthesized by reacting a compound of formula J with a 1,1-disubstituted 2,2,2-trichloroethanol:
• 1,1-disubstituted 2,2,2-trichloroethanol can be used in about 1.5-4 equivalents relative to J, or about 2-3 equivalents relative to J, about 2.5 equivalents relative to J, or about 2.6 equivalents relative to J.
• the reaction is carried out in an organic solvent, preferably an anhydrous solvent, such as anhydrous acetone.
• the reaction can be cooled to 0° C. prior to addition of a strong base, such as NaOH, KOH, or other hydroxide.
• the base is added in about 2-5 equivalents, or about 3-4 equivalents, or about 3.8 equivalents, or about 3.9 equivalents, relative to J.
• the reaction can be allowed to warm to room temperature, and is left at room temperature for about 4-24 h, or about 8-16 h, or about 12 h.
• the product can be purified by standard methods, such as column chromatography or HPLC.
• the invention embraces methods of making hydantoin compounds according to Scheme 2:
• R 1 -L 1 -(C ⁇ O)NH 2 , -L 1 -(C ⁇ O)NHR 4 , -L 1 -(C ⁇ O)NR 4 R 5 , or L 1 -CN for compound 2-I.
• the reactions are analogous to those in Scheme 1, with replacement of thiophosgene with phosgene and replacement of the thioisocyanate F with isocyanate 2-F, resulting in the product hydantoin 2-I instead of the thiohydantoin I.
• phosgene can be replaced with phosgene equivalents such as 1,1-carbonyl diimidazole (see, e.g., the reagents described in Phosgenations—A Handbook , by 141s Cotarca and Heiner Eckert, Weinheim, Germany: Wiley-VCH Verlag GmbH & Co., 2003, particularly the phosgene equivalents listed in Chapter 3).
• phosgene equivalents such as 1,1-carbonyl diimidazole
• R 1 is limited to -L 1 -(C ⁇ O)NH 2 , -L 1 -(C ⁇ O)NHR 4 , and -L 1 -(C ⁇ O)NR 4 R 5 , as hydrolysis of R 1 when R 1 is -L 1 -CN would result in hydrolysis of the other nitrile group present on the other benzene ring.
• L 1 is a nonentity (i.e., a single bond) as hydrolysis is depicted as resulting in a —COOH group, but in other embodiments, L 1 can also be C 1 -C 8 alkylene.
• the present invention comprises a highly efficient process for making a compound of formula (2-I):
• LG is Br, I or another good leaving group, with a compound of formula B:
• the present invention comprises a highly efficient process for making a compound of formula (2-I):
• the compound of formula C is treated with compound E, under amide bond-forming conditions to give the compound of formula G, which is followed by treatment with a reagent such as phosgene to form the compound of formula 2-I (that is, the path C ⁇ G ⁇ 2-I in Scheme 2).
• a compound of formula A is mixed with a compound of formula B in the presence of a catalytic amount of both a copper (I) catalyst and a beta-dione ligand such as 2-acetylcyclohexanone, in a polar solvent and with heating to a temperature of about 90-120° C., about 100-110° C. or about 105° C.
• the copper (I) catalyst can be copper (I) chloride or copper (I) iodide.
• the copper (I) catalyst, such as CuCl can be present in an amount of about 0.05-0.35 equivalents with respect to compound A, about 0.15-0.25 equivalents with respect to compound A, or about 0.2 equivalents with respect to compound A.
• the ligand such as 2-acetylcyclohexanone
• the ligand can be present in an amount of about 0.05-0.35 equivalents with respect to compound A, about 0.15-0.25 equivalents with respect to compound A, or about 0.2 equivalents with respect to compound A.
• the ligand, such as 2-acetylcyclohexanone is present in an amount about equal to the amount of copper (I) catalyst, such as copper (I) chloride, used.
• Compound B can be added in an amount of about 1-2 equivalents with respect to compound A, about 1.25-1.75 equivalents with respect to compound A, or about 1.5 equivalents with respect to compound A.
• the polar solvent can be selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylacetamide (DMA), isopropylacetate (IPAc), isopropyl alcohol (IPA), and the like; in another embodiment, the polar solvent is DMF, water, or a mixture of DMF and water.
• DMSO dimethylsulfoxide
• DMF dimethylformamide
• NMP N-methylpyrrolidone
• DMA dimethylacetamide
• IPAc isopropylacetate
• IPA isopropyl alcohol
• the reaction mixture is then cooled to about 15-25° C., such as to about 25° C. or to room temperature.
• water is added to the cooled reaction mixture followed by washing with a water-immiscible organic solvent such as isopropyl acetate; the mixture is then separated into organic and aqueous layers.
• the aqueous layer is acidified to isolate compound C by precipitation, filtration and drying.
• the compound C is reacted with an alkylating agent of formula R 6 -LG, where R 6 is C 1 -C 8 alkyl and LG is Br, I, or another good leaving group, to form the compound of formula D.
• Compounds of formula R 6 -LG include compounds such as methyl iodide.
• the reaction can be conducted in the presence of an inorganic base, such as K 2 CO 3 , KHCO 3 , Na 2 CO 3 , or NaHCO 3 , in a polar solvent, such as DMSO, DMF, NMP, DMA, or IPAc, and with a catalytic amount of water.
• the catalytic amount of water can be about 5-25%, 10-20%, or 14% of the equivalents of compound C, or about 0.05-0.25%, 0.10-0.20%, or 0.14% of the volume of the polar solvent.
• the reaction mixture can be heated to about 35-50° C. or about 40-46° C., for about 5-60 min, or until analysis shows greater than about 90% or about 95% or about 99% conversion of compound C to compound D.
• the mixture can be cooled to about 5-25° C. or about 15-25° C.
• the reaction mixture containing compound D can be combined with water to precipitate the product D from solution.
• Product D can be isolated by filtration and drying.
• the amount of inorganic base used is about 2 equivalents or less than about 2 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 1.5 equivalents or less than about 1.5 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K 2 CO 3 , is about 1.2 equivalents or less than about 1.2 equivalents relative to compound C.
• CH 3 I when CH 3 I is used to generate D (where R 6 ⁇ CH 3 ) excess CH 3 I is quenched with acetic acid.
• CH 3 I can be used in about 1-1.5 equivalents relative to compound C, such as in an amount of about 1.2 equivalents relative to compound C, and an amount of AcOH can be added in about the amount of, or slightly more than, the excess amount of methyl iodide (for example, when 1.2 equivalents of methyl iodide are used, where methyl iodide is used in 0.2 equivalent excess relative to compound C, then about 0.21-0.25 equivalents, or about 0.23 equivalents, of AcOH relative to compound C can be used) to quench unreacted CH 3 I.
• Alternative methylating agents known to those skilled in the art, such as dimethylsulfate, can also be utilized for this step.
• the step of combining the reaction mixture containing compound D with water is carried out by gradually adding water to the warm reaction mixture over 1-2 h, until about 1-5 volumes of water, or about 1-3 volumes of water, or about 2 volumes of water have been added (relative to the volume of the original reaction mixture), in order to precipitate compound D in a slower manner and reduce the amount of inorganic cation and base, such as K + , and CO 3 2 ⁇ from the inorganic base, such as K 2 CO 3 , that is used in the reaction.
• the precipitated compound D is re-suspended or re-slurried in water, and then the water is removed by filtration, in order to further reduce the amount of inorganic cation present.
• the residual amount of inorganic cation, such as potassium ion, remaining in compound D is less than or equal to about 1000 parts per million (ppm). In another embodiment, the residual amount of inorganic cation, such as potassium ion, remaining in compound D is less than or equal to about 500 ppm. In another embodiment, the residual amount of inorganic cation, such as potassium ion, remaining in compound D is less than or equal to about 300 ppm.
• the residual amount of base, such as bicarbonate ion, carbonate ion, or other base, remaining in compound D is less than or equal to about 1000 parts per million (ppm). In another embodiment, the residual amount of base remaining in compound D is less than or equal to about 500 ppm. In another embodiment, the residual amount of base remaining in compound D is less than or equal to about 300 ppm.
• compound D can be dried by blowing or sucking dry air, dry nitrogen or argon, or other dry inert gas, over the compound. In another embodiment, compound D can be dried by placing the compound under vacuum (such as under about 1 mmHg vacuum or less, 0.5 mmHg vacuum or less, or 0.1 mmHg vacuum or less). In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.5%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.3%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.1%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 500 ppm. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 300 ppm. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 100 ppm.
• An alternative method for formation of compound D from compound C utilizes standard Fischer esterification conditions comprising mixing compound C in methanol and heating for about 1-16 h at about 40-100° C. (or at reflux) with a catalytic amount of acid, such as one to five drops of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, or other mineral acid, p-toluenesulfonic acid, or sulfonic-acid-containing ion exchange resin; in one embodiment, H 2 SO 4 is used. Water can be removed by azeotropic distillation (such as by a Dean-Stark trap) in some embodiments. After esterification is complete (about 70%, about 80%, about 90%, about 95%, or about 99% completion), isolation of compound D can be performed as described above.
• a catalytic amount of acid such as one to five drops of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, or other mineral acid, p-toluenesul
• the step of forming of compound 2-I comprises mixing compound D with compound 2-F in a polar solvent, or a mixture of a first polar solvent and a second polar solvent, and heating to about 60-100° C., about 80-100° C., or about 80-85° C., for a time of about 1-48 h or about 12-24 h.
• the process continues by cooling the reaction mixture to about 15-30° C., to about 25° C., or to room temperature, and combining with water, followed by extracting the desired product with a polar solvent, or a mixture of a third polar solvent and a fourth polar solvent.
• Compound 2-F can be added in an amount of about 1-3 equivalents with respect to compound D, or about 1.5-2.5 equivalents with respect to compound D, or about 1.5 equivalents or about 2 equivalents with respect to compound D, or in an amount of about 1.5 equivalents, followed by an additional portion of about 0.5 equivalents as the reaction progresses.
• the combined organic extract layer can be reduced in volume and seeded with crystals of the desired product 2-I to commence crystallization upon cooling to about 0-10° C. or about 3-6° C., followed by isolating the crystalline product by filtration, and then drying the product by streaming air over the product or in vacuo.
• the polar solvent or the first, second, third and fourth polar solvents, can be selected from the group consisting of DMSO, DMF, NMP, DMA, IPAc, MeCN, IPA, and the like.
• the polar solvent is DMF.
• the first polar solvent is IPAc
• the second polar solvent is DMSO.
• the third polar solvent is IPAc
• the fourth polar solvent is IPA.
• the first polar solvent is IPAc
• the second polar solvent is DMSO
• the third polar solvent is IPAc
• the fourth polar solvent is IPA.
• an alternative method for the formation of compound 2-I involves two steps, outlined in the pathway the path C ⁇ G ⁇ 2-I in Scheme 2.
• the first step utilizes standard amide-bond formation conditions, comprising for example treating compound C with a coupling reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (AOP), benzotriazol-1-yloxytris(pyrrolidine)phosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxytris(pyrrolidine)phosphonium
• the polar solvent is, or the first and second polar solvents are, selected from the group consisting of DCM, DMSO, DMF, NMP, DMA, MeCN, and the like.
• the second step comprises a ring-closure reaction of compound G with a carbonylation reagent such as phosgene, and heating the neat solution to about 60-120° C.
• the reaction is performed in a sealed-tube apparatus.
• Phosgene or a phosgene equivalent for example, carbonyl diimidazole
• compound 2-I can be subjected to hydrolytic conditions when R 1 is a primary or secondary amide group, to produce the corresponding carboxylic acid derivative.
• substituent R 1 of the compound of formula A is —C( ⁇ O)—NH—R 4 .
• R 1 is —C( ⁇ O)—NH—CH 3 .
• substituent R 2 of the compound of formula A is fluorine.
• R 1 is —C( ⁇ O)—NH—R 4 and R 2 is fluorine.
• R 1 is —C( ⁇ O)—NH—CH 3 and R 2 is fluorine, and the compound of formula A is 4-bromo-2-fluoro-N-methylbenzamide.
• the compound of formula B is 2-aminoisobutyric acid (i.e., Y 1 and Y 2 are each CH 3 ). In another embodiment of the above method, the compound of formula B is 1-aminocyclobutanecarboxylic acid. In another embodiment of the above method, the compound of formula B is 1-aminocyclopentanecarboxylic acid.
• Y 1 and Y 2 are each CH 3 , R 1 is —C( ⁇ O)NHCH 3 and/or R 2 is F.
• Y 1 and Y 2 are each CH 3 , R 1 is —C( ⁇ O)NH 2 and/or R 2 is F.
• Y 1 and Y 2 are each CH 3 , R 1 is replaced by a —C( ⁇ O)OH group, and/or R 2 is F.
• Variations of the compound of formula (2-I) are also provided.
• Compounds of formula (2-I) or a variation thereof as detailed herein or a pharmaceutically acceptable salt of any of the foregoing may find particular use in the treatment of prostate cancer, including CRPC and/or hormone-sensitive prostate cancer.
• the final product can be synthesized as follows:
• compound C is reacted with compound 2-F (4-isocyanato-2-(trifluoromethyl)benzonitrile) to form product 2-M.
• the reaction can be run under basic conditions, with a trialkylamino base such as triethylamine present in about 2-5 equivalents, or about 3-4 equivalents, or about 3.4 equivalents, relative to compound C.
• Compound 2-F, 4-isocyanato-2-(trifluoromethyl)benzonitrile can be present in amounts of about 1.1-4 equivalents, or 1.1-2 equivalents, or about 1.5 equivalents, relative to compound C; alternatively, about 1.5 equivalents of compound 2-F can be added, followed by another portion of about 0.5 equivalents as the reaction progresses.
• the solvent can be ethanol or another alcohol.
• the reaction mixture can be stirred for about 4-16 days, about 8-12 days, or about 10 days, at room temperature or elevated temperature. Afterwards, the reaction mixture can be concentrated, mixed with aqueous acid such as 1M HCl, and the product extracted with an organic solvent, such as ethyl acetate, to obtain the product 2-M.
• aqueous acid such as 1M HCl
• organic solvent such as ethyl acetate
• the compound C is synthesized by reacting a compound of formula J with a 1,1-disubstituted 2,2,2-trichloroethanol:
• 1,1-disubstituted 2,2,2-trichloroethanol can be used in about 1.5-4 equivalents relative to J, or about 2-3 equivalents relative to J, about 2.5 equivalents relative to J, or about 2.6 equivalents relative to J.
• the reaction is carried out in an organic solvent, preferably an anhydrous solvent, such as anhydrous acetone.
• the reaction can be cooled to 0° C. prior to addition of a strong base, such as NaOH, KOH, or other hydroxide.
• the base is added in about 2-5 equivalents, or about 3-4 equivalents, or about 3.8 equivalents, or about 3.9 equivalents, relative to J.
• the reaction can be allowed to warm to room temperature, and is left at room temperature for about 4-24 h, or about 8-16 h, or about 12 h.
• the product can be purified by standard methods, such as column chromatography or HPLC.
• the invention embraces a process for preparing a compound of formula (I, 2-Ia):
• X is S or O; Y 1 and Y 2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R 7 is L 1 -COOH, where L 1 is a single bond or C 1 -C 8 alkylene; and R 4 and R 5 are independently selected from H and C 1 -C 8 alkyl; and R 2 is hydrogen or fluoro; said process comprising reacting the compound of formula Aa:
• LG is a leaving group, Br, or I; with the compound of formula B:
• R 6 is C 1 -C 8 alkyl
• X is S. In another embodiment, X is O.
• L 1 can be a single bond; and R 7 can —C( ⁇ O)—OH.
• Y 1 and Y 2 can both be methyl, R 7 can be —C( ⁇ O)—OH, and R 2 can be F.
• compositions of any of the compounds detailed herein are embraced by this invention.
• the invention includes pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
• Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, subcutaneous, intramuscular, intravenous, nasal, topical or rectal administration, or a form suitable for administration by inhalation.
• pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
• Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
• “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
• Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion such as potassium or sodium, an alkaline earth ion such as calcium, or an aluminum ion; or coordinates with an organic base.
• a metal ion e.g., an alkali metal ion such as potassium or sodium, an alkaline earth ion such as calcium, or
• Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
• Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
• Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 January; 66(1):1-19.
• Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
• a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
• Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
• Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
• excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
• a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
• Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
• Alkyl refers to and includes saturated linear, branched, or cyclic hydrocarbon structures and combinations thereof. Particular alkyl groups are those having 1 to 12 carbon atoms (a “C 1 -C 12 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C 1 -C 8 alkyl”).
• butyl is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclobutyl;
• propyl includes n-propyl, iso-propyl and cyclopropyl. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl and the like.
• Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl.
• a cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof.
• a preferred cycloalkyl has from 3 to 12 annular carbon atoms.
• a more preferred cycloalkyl has from 3 to 7 annular carbon atoms (a “C 3 -C 7 cycloalkyl”).
• Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl and the like.
• Substituted alkyl refers to an alkyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkyl
• leaving Groups are those groups which depart with a pair of electrons in heterolytic bond cleavage, such as occurs during nucleophilic substitution.
• Good leaving groups include, for example: Cl, Br, I, triflates, diazonium salts, fluorosulfonates, tosylates, and mesylates.
• the particular leaving groups include Cl, Br, or I. More particular groups include Br, or I.
• the present invention comprises a highly efficient process for manufacture of diarylthiohydantoin compounds of formula (I):
• Y 1 and Y 2 are each CH 3 , R 1 is —C( ⁇ O)NHCH 3 and/or R 2 is F. In one embodiment, Y 1 and Y 2 are each CH 3 , R 1 is —C( ⁇ O)NHCH 3 and R 2 is F. In another embodiment, Y 1 and Y 2 are each CH 3 , R 1 is —C( ⁇ O)NH 2 , and/or R 2 is F.
• Y 1 and Y 2 are each CH 3 , R 1 is —C( ⁇ O)NH 2 , and R 2 is F. In another embodiment, Y 1 and Y 2 are each CH 3 , R 1 is replaced by —C( ⁇ O)OH, and/or R 2 is F. In another embodiment, Y 1 and Y 2 are each CH 3 , R 1 is replaced by —C( ⁇ O)OH, and R 2 is F. In another embodiment, Y 1 and Y 2 , together with the carbon to which they are bonded, form a cyclobutane ring, R 1 is replaced by —C( ⁇ O)OH, and/or R 2 is F.
• Y 1 and Y 2 together with the carbon to which they are bonded, form a cyclobutane ring, R 1 is replaced by —C( ⁇ O)OH, and R 2 is F.
• Y 1 and Y 2 together with the carbon to which they are bonded, form a cyclobutane ring, R 1 is —C( ⁇ O)NH 2 , and/or R 2 is F.
• Y 1 and Y 2 together with the carbon to which they are bonded, form a cyclobutane ring, R 1 is —C( ⁇ O)NH 2 , and R 2 is F.
• Y 1 and Y 2 together with the carbon to which they are bonded, form a cyclobutane ring, R 1 is —C( ⁇ O)NHCH 3 , and/or R 2 is F.
• Y 1 and Y 2 together with the carbon to which they are bonded, form a cyclobutane ring, R 1 is —C( ⁇ O)NHCH 3 , and R 2 is F.
• the synthesis as outlined above comprises a method of synthesizing compound C, which comprises mixing a commercially available variant of compound A with compound B in the presence of a catalytic amount of both a copper (I) catalyst and a ligand such as acetylcyclohexanone, in a polar solvent and with heating of the reaction mixture, followed by cooling, adding water and washing with organic solvent, then acidifying the aqueous layer to isolate the desired product C by precipitation, filtration and drying.
• Copper catalysts for use in the invention can be chosen from the group consisting of copper (I) chloride and copper (I) iodide. Copper (I) chloride is typically used (Cai et al., Synthesis (Thieme Publishing Group) 2005, No. 3, pp. 496-499).
• Compound D can be synthesized by a method which comprises mixing the acid C with an alkylating agent such as methyl iodide and an inorganic base in a polar solvent and a catalytic amount of water, and heating, then cooling the mixture and combining with water, whereupon the product D precipitates from solution and is isolated by filtration and drying.
• An alternative method for this procedure utilizes standard Fischer esterification conditions comprising mixing acid C in methanol and heating with catalytic mineral acid, followed by isolation as described above.
• the inorganic base for the alkylation can be selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate, typically potassium carbonate.
• the mineral acid for the Fischer esterification can be chosen from the group consisting of sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid, typically sulfuric acid.
• Moisture also adversely affects the reaction of compound D with compound F to form compound I. Moisture can be removed from compound D by blowing dry air, dry nitrogen, dry argon, or other dry gas over the compound, by placing the compound on a filter (such as a sintered glass funnel) and pulling air or other dry gas through the compound, or by placing the compound under vacuum for a period of time.
• a filter such as a sintered glass funnel
• Compound I can be synthesized by mixing compound D with compound F in a mixture of a first polar solvent and a second polar solvent, and heating, then cooling the mixture and combining with water, extracting the desired product with a mixture of a third polar solvent and a fourth polar solvent.
• the combined organic extract layer is reduced in volume and seeded with crystals of the desired product I to commence crystallization upon cooling, whereupon the crystalline product is isolated by filtration and drying.
• the first, second, third and fourth polar solvents can be selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylacetamide (DMA), isopropylacetate (IPAc), isopropyl alcohol (IPA), and the like.
• DMSO dimethylsulfoxide
• DMF dimethylformamide
• NMP N-methylpyrrolidone
• DMA dimethylacetamide
• IPAc isopropylacetate
• IPA isopropyl alcohol
• the product I can be subjected to the process of crystallization by preparing a saturated solution in an organic solvent or solvent mixture thereof, by concentrating the solution, optionally adding a seed of product I, and cooling the solution to a temperature range and maintaining the solution at that temperature range for a sufficient period till the crystallization of product I is completed.
• This process of crystallization can be carried out at a temperature range of about 0-80° C., typically 0-10° C.
• Compound I can also be synthesized by first treating compound C with a coupling reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and the like, with compound E, in a polar solvent or a mixture of a first polar solvent and a second polar solvent to give compound G, which is then treated with excess thiophosgene with heating to produce compound I.
• DCC dicyclohexylcarbodiimide
• DIC diisopropylcarbodiimide
• EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
• Thiophosgene can be present in an amount of about 1-10 equivalents with respect to compound G, or about 5 equivalents with respect to compound G.
• the polar solvent can be selected from the group consisting of DCM, DMSO, DMF, NMP, DMA, MeCN, and the like.
• Compound I can be subjected to hydrolytic conditions when R 1 is a primary, secondary or tertiary amide group, to produce the corresponding carboxylic acid derivative.
• a method for synthesizing compound F comprises mixing a commercially available variant of compound E with thiophosgene in a mixture of an organic solvent, such as a non-polar solvent, and water at ambient temperature, adding water, and separating the isothiocyanate compound product F.
• the combined organic extract layer is reduced in volume and a second organic solvent, such as a non-polar solvent, is added to commence crystallization upon seeding with crystals of desired product F, whereupon the crystalline product is isolated by filtration and drying.
• the organic solvent can be selected from the group consisting of dichloromethane (DCM), toluene, chloroform, hexanes, heptane and 1,4-dioxane, more preferably DCM or heptane.
• DCM dichloromethane
• Thiophosgene can be used in the amount of about 1-1.5 mol, such as 1.1 mol, per mole of aniline E.
• the thiophosgene can be added over a period of time ranging from 30 min to 2 h, such as 1 h.
• the product F can be subjected to the process of crystallization by preparing a saturated solution in an organic solvent or solvent mixture thereof, by concentrating the solution, and cooling the solution to a temperature range and maintaining the solution at that temperature range for a sufficient period till the crystallization of product F is completed.
• the process of crystallization can be carried out at a temperature range of about 0° C. to about 50° C., about 10° C. to about 40° C., about 20° C. to about 30° C., or about 20° C. to about 25° C., or about 25° C.
• the organic solvent used for crystallization can be n-heptane, or a mixture of n-heptane and IPAc.
• IPAc in n-heptane can be used, or about 0.20 mol % to about 0.55 mol % of IPAc in n-heptane can be used, or about 0.03 to about 0.06 weight percent of IPAc in n-heptane can be used, or about 0.20, about 0.36, about 0.37, about 0.38, about 0.41, about 0.54, or about 0.55 mol % of IPAc in n-heptane can be used.
• the crystallization solution of F can be seeded with small amounts of previously isolated F to help induce crystallization, for example about 0.2 to 0.5% by weight of the theoretical amount of F to be obtained.
• the amount of F used for seeding can range from about 0.20% to about 0.50% (% by weight) of the amount of F sought to be recrystallized, such as about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, or about 0.50%.
• the solutions/slurries can be cooled to about 0° C. to about 5° C. over a period of about 0.5 to about 2 hours, or about 1 hour.
• the solutions can also be stirred with high or low agitation, such as from about 200 rpm to about 400 rpm, about 300 rpm to about 400 rpm, about 200 rpm to about 400 rpm, or at about 200, about 300, or about 400 rpm.
• high or low agitation such as from about 200 rpm to about 400 rpm, about 300 rpm to about 400 rpm, about 200 rpm to about 400 rpm, or at about 200, about 300, or about 400 rpm.
• the solid can then be filtered, washed with cold n-heptane (about 10 to 30 mL, or about 20 mL), and vacuum dried at about 20° C. to about 25° C.
• the conversion to the acid chloride was found to be 99.9% (the acid chloride intermediate was quenched with N-propylamine prior to analysis). After stirring for an additional 1 h at 70-72° C., the batch was cooled to 10° C. over 1 h.
• n-Heptane (18 L, 10 vol) was added to the reactor and the mixture was distilled to 8 L (4.4 vol) over 6 h (30-35° C., 100-200 mbar, 1.5-2.9 psi). At this stage the IPAc/n-heptane ratio was 26:1.
• the resulting slurry was allowed to stir for 12 h at 25° C. before cooling to 5-10° C. over 1 h.
• the batch was stirred for 1.5 h at 5-10° C. before filtering, rinsing with n-heptane (2 ⁇ 1 vol) and air-drying.
• the filter cake (1.87 kg) was vacuum dried at 55-60° C. for 141 h to yield 1.72 kg (90% yield) of desired amide product A-2 with an HPLC purity of 99.5%, and 0.2% H 2 O.
• the reaction mixture was then cooled to RT and extracted with water (120 mL) and IPAc (60 mL). The lower aqueous layer was re-extracted with IPAc (60 mL) and acidified with 180 mL of 1M citric acid to a pH of 4.0. The product began to crystallize at RT and the batch was further cooled to 5-7° C., filtered, washed with water (40 mL) and dried under vacuum at 50° C. for 12 h. The reaction yielded 8.3 g of product C-1 (75.4% yield) as a tan solid with HPLC purity of 99.6%.
• the solution was next diluted with IPAc (900 mL, 6 vol) and washed with DI water (450 mL, 3 vol) and IPA (225 mL, 1.5 vol) was used to break the emulsion.
• the organic phase was then concentrated to 4.5 volumes (675 mL) under reduced pressure at 30-35° C.
• the solution was next diluted with IPA (2000 mL, 13.3 vol) and heated to 75-82° C. (jacket temperature of 95° C.). While heating, the solution was slightly cloudy, but became clear at 70-71° C.
• the solution was then concentrated to 8 volumes (1200 mL) under atmospheric pressure maintaining 77-82° C.
• HPLC Column, YMC ODS AQ, 4.6 ⁇ 250 mm, 5 ⁇ m, Mobile Phase A: 10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, Isocratic: 55% A:45% B, Retention time, 3.804 mM, HPLC Purity, 95.82%, Flow Rate, 1 mL/min.
• 1 H NMR (CDCl 3 , FREEBASE): ⁇ (ppm) 8.22 (t, 1H), 8.0 (d, 1H), 7.98 (s, 1H), 7.82 (d, 1H), 7.2 (m, 2H) 1.6 (s, 6H).
• Methylpropionic acid derivative C-1 (0.254 g, 1 mmol) was dissolved in DCM (15 mL) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.380 g, 2.0 mmol), followed by slow addition of 4-amino-2-(trifluoromethyl)benzonitrile (0.200 g, 1.1 mmol). The mixture was stirred at RT for 5-6 h. After analysis of the reaction by LCMS and TLC, the mixture was extracted with DCM and the extracts washed with water, dried and evaporated. The crude product was purified by chromatography to yield the desired product G-1 (0.150 g, 36% yield).
• Aqueous layer was made acidic by adding 1M citric acid solution (pH ⁇ 4).
• the product was extracted with ethyl acetate (3 ⁇ 200 mL).
• Combined organic layer was dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to afford 16 g of 4-(2-carboxypropan-2-ylamino)-2-fluorobenzoic acid as crude product. This crude material was used as such for the next example.

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